Recent advances on natural depsidones: sources, biosynthesis, structure-activity relationship, and bioactivities

Depsidones are a class of polyphenolic polyketides that have been proposed to be biosynthesized from oxidative coupling of esters of two polyketidic benzoic acid derivatives. They are principally encountered in fungi and lichens. In addition to their diversified structural features, they revealed varied bioactivities such as antimicrobial, antimalarial, cytotoxic, anti-inflammatory, anti-Helicobacter pylori, antimycobacterial, antihypertensive, anti-diarrheal, antidiabetic, phytotoxic, anti-HIV, anti-osteoclastogenic, and butyrylcholinesterase, tyrosinase, hyaluronidase, and acetylcholinesterase inhibition. The current work was targeted to provide an overview on the naturally reported depsidones from various sources in the period from 2018 to the end of 2022 including their structures, biosynthesis, sources, and bioactivities, as well as the reported structure-activity relationship and semisynthetic derivatives. A total of 172 metabolites with 87 references were reviewed. The reported findings unambiguously demonstrated that these derivatives could be promising leads for therapeutic agents. However, further in-vivo evaluation of their potential biological properties and mechanistic investigations are needed.


INTRODUCTION
Nature affords unlimited riches of novel biomolecules that are derived from living organisms, including animals, plants, and microorganisms (Abdel-Razek et al., 2020). These metabolites have played a fundamental role for thousands of years as remediation for various human illnesses because of their availability and low cost, particularly in developing countries. Also, their chemical diversity with broad bioactivities makes them these compounds may draw the interest of medicinal and synthetic chemists for the synthesis and discovery of new agents utilizing known depsidones as start materials.

METHODOLOGY
The published data on depsidones was obtained by searching articles on various databases and Publishers such as Google-Scholar, PubMed, Science Direct, Bentham, Thieme, Springer, Scopus, Taylor/Francis, and Wiley. The search was done utilizing the keywords: "Depsidone + Lichens", OR "Depsidone + Fungi", OR "Depsidone + Plant" OR "Depsidone + Biological activity" OR "Depsidone + Biosynthesis" OR "Depsidone + Semisynthesis" OR "salazinic acid", "protocetraric acid", "lobaric acid". This work included the English language published articles in peer-reviewed journals in the period from 2018 to the end of 2022. The published articles reported new biological evaluation of metabolites reported before 2018 had been included. A total of 83 articles had been reviewed. The no full access (e.g., conference proceedings), irrelevant, and non-reviewed journals published articles had been excluded. For the non-English articles, the data are extracted from the English abstracts.

BIOACTIVITIES OF DEPSIDONES
The reported depsidones were assessed for various bioactivities . It is noteworthy that some of the reported metabolites had more powerful efficacy than the positive controls. The results of the reported bioactivities were listed and discussed below.

Antimicrobial activity
Currently, antibiotic resistance of microbes has become one of the utmost serious menaces to human health (Fjell et al., 2012). The global amplification and rapid growth of multi-resistant microbes that are untreatable with the current antimicrobial therapy have been associated with growing morbidity and mortality rates (Dhingra et al., 2020). Despite, immense knowledge of this universal health dilemma, developing new-generation antibiotics that combat these microbes has been proven to represent a significant defy (Bahar & Ren, 2013). In this regard, many natural metabolites have gained much attention from scientific and pharmaceutical communities because of their antibiotic potential (Khameneh et al., 2019). The majority of reported depsidones were assessed for their capacities on various pathogens including antitubercular, anti-phytopathogenic, antimalarial, and antibacterial activities. In many studies, they possessed a broad range of activity.

Cytotoxic activity
Some of the reported depsidones were assessed for their cytotoxic capacities against different cancer cell lines that were highlighted below, and the results of the potential metabolites were listed in Table S4.
Also, Koo et al. (2022) reported that in the MTS assay of 130 and 131 against HCT-116 cells, 131 showed potent cytotoxic potential (EC 50 1.11 mM) than 5-fluorouracil (EC 50 9.4 mM), suggesting its potential as an anticancer lead against colon cancer. Additionally, physodic acid (134) identified from Hypogymnia physodes European lichen (Fig. 11) was found to exhibit cytotoxic potential against A-172, T98G, and U-138 MG cell lines (IC 50 s 42.41, 50.57, and 45.72 mM, respectively) in the MTT assay (Studzi nska-Sroka et al., 2021). Additionally, Cardile et al. investigated 134`s potential on DU-145 and LNCaP cell growth and its apoptotic capacity on TRAIL-resistant LNCaP cells in combination with TRAIL (tumor-necrosis factor-related apoptosis-inducing ligand) using MTT assay. Lactate dehydrogenase (LDH) release is a marker of membrane breakdown. It prohibited both cell viability (Conc. 12.5-50 mM) without affecting normal cells and no observed increase in LDH (lactate dehydrogenase) level, which is a marker for membrane integrity. In addition, it activated apoptosis and raised ROS formation. Interestingly, it sensitized LNCaP cells to TRAIL-produced apoptosis. Thus, combining 134 with other anti-prostatic cancer drugs could be a prominent treatment strategy that required further studies (Cardile et al., 2022). Anh et al. (2022) stated that 138, 139, 143, 146, 147, 155-157, and 160 were found to have cytotoxic potential against PC-3, NCI-H23, HCT-15, NUGC-3, ACHN, and MDA-MB-231 with IC 50 s ranging from 3.4 to 27.7 µM, whereas 138, 139, and 143 were the most potential metabolites (IC 50 s 3.4-6.2 µM). It was observed that the number of chlorine and substitution had no significant effect on activity, while free C-4-OH (157) was substantial for activity. Zwartsen et al. (2019) reported that 138 and 151 reduced MDA-MB-231 cell viability (Conc. M50 mM), while they did not affect cell proliferation (Fig. 12). Additionally, they caused MDA-MB-231 cell cycle arrest (Conc. 100 mM). It is noteworthy that 138 potency was less than 151, this variation may be due to two bromine atoms in 151 compared to 138 that enabled the halogen bonds formation (Fig. 12).

Anti-inflammatory activity
Inflammation is a complicated defense process, which is induced by pro-inflammatory cytokines secretion by macrophages as a result of stimuli (e.g., infectious agent, tissue ischemia, injury, etc.) (Zhao et al., 2021a;Liang et al., 2022). Impairment of the pro-inflammation mediator secretion can lead to diverse disorders such as asthma, atherosclerosis, psoriasis, periodontal diseases, carcinogenesis, and rheumatoid arthritis (Chen et al., 2018a;Niu et al., 2021b).
Also, polyanthadepsidone A (1), a new highly methylated depsidone from the Garcinia polyantha leaves dichloromethane extract exhibited in vitro suppressive influence on the oxidative burst by serum opsonized zymosan in the whole blood (Lannang et al., 2018).
Chemical investigation guided by HPLC/DAD of the EtOAc extract of the marine-derived Curvularia sp. IFBZ10 resulted in new depsidones; 30-35 that were separated by SiO 2 CC/HPLC and their structures and absolute configuration were determined by spectral analyses as well as TDDFT/ECD (time-dependent density functional theory/electronic circular dichroism) and DFT/NMR (density functional theory/nuclear magnetic resonance) calculations (Duong, 2019). The anti-inflammation potential of 30, 31, 34, and 35 was assessed by measuring IL-1β production inhibition in Propionibacterium acnes-induced THP-1 cells. Compound 31 exhibited noticeable IL-1β production inhibition (IC 50 7.47 mM) compared to retinoic acid (IC 50 3.38 µM), while 30 and 35 (IC 50 18.83 mM) had no and moderate efficacy, respectively revealing that stereo-configuration had a substantial role in the activity. Further, 31 prohibited the IL-1β production by selectively minimizing the JNK and ERK phosphorylation. The molecular docking implied that 31 suppressed IL-1β production via binding to the TLR2/1 protein active site (Ding et al., 2019). Compounds 7, 34, and 82-84 revealed anti-inflammation potential (IC 50 s 19.4-34.4 mM) on NO formation induced by LPS in RAW264.7 macrophages, where 7 and 83 had potent potential (IC 50 s 22.6 and 19.9 mM, respectively) relative to PDTC (IC 50 23.1 mM, ammonium pyrrolidine dithiocarbamate) (Chen et al., 2020) (Table S5). Hao et al. (2022) purified compound 55, a new tetracyclic derivative from mangrove-associated Aspergillus sp. GXNU-A9 EtOAc extract utilizing SiO 2 CC and HPLC. This metabolite (IC 50 8.22 mM) displayed a noticeable NO production inhibition capacity in RAW 264.7 cells boosted by LPS compared to dexamethasone (IC 50 5.62 mM). In another study, He et al. (2022) investigated Melastoma malabathricum subsp. normale roots utilizing SiO 2 /RP-18/Sephadex LH-20 CC/HPLC, resulting in a new derivative, guanxidone B (56) together with 12, 51, and 55. Their structures were elucidated by spectral and CD analyses. Compounds 55 and 56 possessed marked anti-inflammation efficacy (IC 50 s 6.46 to 9.82 µM, respectively) via suppressing NO production utilizing Griess Reagent System compared to dexamethasone (IC 50 2.52 µM). Compound 56 was structurally similar to 51 having C-4 CH 2 OH instead of C-4 CH 3 in 51. It is noteworthy that 56 had better activity than 55, indicating that CH 3 O at C-4 affected the activity (He et al., 2022).

Anti-Helicobacter pylori activity
The inhibition of Helicobacter pylori urease activity is an effective strategy for treating this infectious disease. From Cladonia rappii acetone extract, 44 was separated by crystallization ((CH 3 ) 2 CO:CHCl 3 20:1) and identified by spectral data. This compound was a marked competitive inhibitor of jack bean urease uricolytic activity. Also, it had a potent (MICs 0.034 to 0.068 mM) growth inhibition effectiveness against six clinical isolates of H. pylori than omeprazole (MICs 0.046-0.093 mM) in the broth microdilution assay. Therefore, 44 could be further developed for treating H. pylori-linked infections (Lage et al., 2018).

Antidiabetic activity
Diabetes mellitus is a worldwide rapidly disseminated metabolic disorder that is distinguished by persistent hyperglycemia because of the flaw in insulin action, insulin secretion, or both (Devi et al., 2020). Unrestrained hyperglycemia promotes protein glycation product formation (advanced-glycation-end products, AGEs). AGEs immoderate accumulation in diabetics enhances diabetic complication pathogenesis, including nephropathy, retinopathy, cardiomyopathy, and neuropathy. It was estimated that the number of diabetic patients has been rose from 108 million in 1980 to 422 million in 2014 (Zheng, Ley & Hu, 2018). In 2015, five million deaths were reported due to diabetes and its related complications, making it 9th causal factor of diminished life expectancy (Abubakar, Tillmann & Banerjee, 2015). In 2019, two million deaths were recorded caused by diabetes, and kidney diseases resulted from diabetes (World Health Organization, 2021).
The available oral synthetic antidiabetics e.g., thiazolidinediones, biguanides, meglitinides, and sulfonylureas were reported to produce unwanted effects (Lorenzati et al., 2010). Thus, searching for new targets and approaches for treating diabetes is extremely recommended. a-Glucosidase (AG) is one of the fundamental enzymes implicated in carbohydrate digestion. It has been proven as an efficient target for diabetes management. However, the usage of the available alpha-glucosidase inhibitors (AGIs) such as miglitol, voglibose, 1deoxynojirimycin, and acarbose has frequently been accompanied by side effects, in addition to the high costs. Many studies were carried out for identifying and validating the potential of natural products as AGIs for the prevention or curing of diabetes (Assefa et al., 2019).

Antihypertensive activity
RhoA (Ras homolog-gene family-member-A) is a member of the Rho-GTPase superfamily that was originally found to promote migration and cell cycle progress in cancer cells and control actin dynamics that are substantial for preserving the cell's cytoarchitecture. It had been reported to have a marked role in cardiomyopathies and cardiac remodeling (Kilian et al., 2021). Also, the inhibition of RhoA activation reduced the angiotensin II-dependent hypertension development (Olivon et al., 2018). Olivon et al. identified the new metabolite,baillonic acid (20) along with 59 from New Caledonian Meiogyne baillonii bark EtOAc extract. Only 59 exhibited a significant RhoA-p115 complex GDP/GTP exchange inhibition potential (IC 50 187 mM, 50.5% inhibition) in the Biacore assay, thus it could have a potential for treating high blood pressure (Olivon et al., 2018).

Anti-diarrheal activity
CFTR (cystic fibrosis transmembrane conductance regulator) is a cAMP-activated chloride channel that is accountable for the trans-epithelial secretion of chloride, resulting in the promoting force for intestinal fluid secretion (Li & Naren, 2010). The CFTR's excessive function leads to secretory diarrhea, therefore its prohibition minimized intestinal fluid secretion. The CFTR inhibitory potential of 138, 139, 141, 146, 147, 150, 157, 160, and 164 in T84 cell monolayers using short-circuit current analysis was estimated. It is noteworthy that 138,139,141,147,150,157, and 160 had remarkable (concentration 10 mM, >50% inhibition) CFTR-mediated chloride secretion inhibition where 160 and 157 were the most powerful. Compounds 157 and 160 dose-dependently prohibited forskolin-boosted chloride secretion in T84 cells (IC 50 s 0.5 and 2.0 mM, respectively) with almost complete suppression at concentrations of 20 and 10 mM, respectively, whereas 157 was more potent than 160. Further investigation of 157 for their effect on CT (cholera toxin)-boosted chloride secretion across T84 cells. CT is an enterotoxin accountable for massive symptoms of cholera patients' diarrhea. Compound 157 was found to dose-dependently prohibit CT-induced chloride secretion (IC 50 5.0 mM) with complete prohibition at a concentration of 100 mM. These findings revealed an anti-secretory potential of 157 and 160 that could be beneficial for diarrhea treatment (Phainuphong et al., 2018).

BChE (butyrylcholinesterase) and AChE (acetylcholinesterase), and phosphodiesterase inhibition activities
Neurodegenerative illnesses, such as Alzheimer's (AD) or Parkinson's disease (PD) represent a critical global health concern. They are a series of procedures that result in the gradual forfeiture of neuronal function and nerve cell death (Di Paolo et al., 2019). BChE (butyrylcholinesterase) and AChE (acetylcholinesterase) are substantial for CNS functions that hydrolyze acetylcholine . Acetylcholine hydrolysis suppression is substantial in neuro-degenerative illnesses. Moreover, BChE and AChE noncholinergic actions like the impact on cellular adhesion and proliferation process regulation are also crucial in brain tumors . Rukachaisirikul et al. (2019) stated that 23 and 27 possessed PDE5 (−5) inhibition capacity (% inhibition 84% and 89% and IC 50 s 5.69 and 9.96 mM, respectively). Studzi nska-Sroka et al. investigated 134 AChE and BChE inhibition potentials using Ellman's colorimetric method. It only prohibited BChE (%inhibition 8.1%) (Studzi nska- . Compound 148 reported from A. unguis displayed AChE inhibition potential (IC 50 102.4 µM),while 138,139,146,147,150, and 153 had weak or no effectiveness (Yang et al., 2018).

Tyrosinase and hyaluronidase inhibitory activities
Hyaluronic acid (HA) is a brain-extracellular matrix prime component that is generated by Hyaluronan synthase (HAS) and broken down into fragments by hyaluronidase (Misra et al., 2011). The resulting fragments were reported to be related to enhanced cancer cell invasion capability and proliferation, as well as proangiogenic and proinflammation processes (Chen et al., 2018b).
Tyrosinase oxidizes surplus dopamine to form dopamine quinones, quite reactive species that promote cell death and neural damage. It is implicated in neurodegenerationrelated illnesses like Parkinson's disease (Chen et al., 2018b). Thus, its prohibition is targeted to discover new drugs for these disorders, particularly Parkinson's disease. Compound 134 showed 25% inhibition of tyrosinase enzyme (Conc. 1.6 mg/mL), which was 3-times lower than azelaic acid using L-DOPA (substrate) (Studzi nska-Sroka et al., 2021).

Anti-osteoclastogenic activity
Bone homeostasis is maintained and regulated by two metabolic processes, bone formation by osteoblasts and bone resorption by osteoclasts (Jacome-Galarza et al., 2019). Osteoclast differentiation is controlled by two factors, the M-CSF (macrophage colony stimulation factor) and RANKL (receptor activator of the nuclear factor kappa-B ligand). Signaling pathways of RANKL are considered key targets for prohibiting bone resorption and osteoclast differentiation (Tan et al., 2020). NF-κB has a pivotal function in RANKL-caused osteoclast differentiation . Zhang et al. (2022) investigated the inhibitory potential of 147, 149, 150, and 154 on RANKL-induced osteo-clastogenesis in RAW264.7 macrophages and BMMs (bone marrow macrophage cells) using luciferase reporter gene and TRAP (tartate-resisant acid phosphatase) assays, respectively. It was found that 147, 149, and 154 demonstrated prohibition of LPS-caused NF-κB activation in RAW264.7 macrophages (Conc. 20 mM).
GnRH (Gonadotropin-releasing hormone) antagonistic activity Nguyen et al. (2022b) proved that the treatment of female rats with lobaric acid (136) (50 and 100 mg/kg b.w./day) significantly ameliorated tetramethrin (50 mg/kg b.w/day)induced alteration on estrous cycle. It reversed gonadotropins serum levels through influencing the pituitary/hypothalamic axis and competitively inhibited tetramethrin binding to GnRH receptor in both thermodynamic and kinetic processes.

CONCLUSION
Natural metabolites biosynthesized by various living organisms are renowned for their vital contribution to drug design and discovery. In this work, a total of 172 depsidones were reported from various sources from 2018 to 2022 with a greater number separated in 2022. The major depsidone derivatives are reported from fungi (107 compounds, 62.2%), then lichens (52 compounds, 30.3%), and the least number of depsidones were reported from plant sources (13 compounds, 7.5%). These metabolites were commonly separated from the species belonging to the following genera: Aspergillus, Chaetomium, and Spiromastix (fungi); Usnea, Parmotrema, and Ramalina (lichens), and Melastoma, Hypericum, and Garcinia (plants).
These metabolites were evaluated for various bioactivities mainly antimicrobial, cytotoxic, and antidiabetic capacities. Depsidones could have the potential as lead metabolites for neurodegenerative illnesses and diabetes through their inhibition of butyrylcholinesterase, tyrosinase, a-glucosidase, and acetylcholinesterase enzymes. Besides, 127 could be a potential lead for bactericides to control rice bacterial-blight disease. Also, 44 demonstrated powerful anti-H. pylori potential that could be further developed for treating H. pylori-linked infections. It was found that the ring substation patterns greatly influenced the activities as highlighted in some reports on structure-activity relation (Shukla et al., 2019;Niu et al., 2021b).
Preparation of semi-synthetic derivatives from these compounds resulted in derivatives with more powerful activity than parent compounds e.g., unguinol and nidulin, which could encourage medicinal chemists to carry out further modification of the structures of other reported metabolites and assess the effect of this modification on the bioactivities. Besides, altering cultural media conditions could be an efficient strategy to get novel biometabolites. Also, the co-culturing of two or more organisms from different species (3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazoliuminner salt) MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide TM4 cells Murine Sertoli cells NCI-H460 Human non-small cell lung cancer cell line NCI-H187 Human small-cell lung cancer NCI-H23 Human lung cancer cell line NF-κB

5-Lipooxygenase
Nuclear factor kappa-light-chain-enhancer of activated B cells NMR Nuclear magnetic resonance NUGC-3 Human stomach cancer cell line NO Nitric oxide PC-3 Human prostatic-testosterone-independent cell line PDE5 Phosphodiesterase